Project Summary/Abstract Chronic kidney disease (CKD) patients are at significantly higher risk of cardiovascular (CV) mortality. One prominent feature of CKD that is independently associated with increased CV risk is exercise intolerance. Our prior studies show that CKD patients have an exaggerated increase in blood pressure (BP) during both moderate and low-intensity exercise. Such exaggerated BP responses could contribute to an increased risk of CV events not only during exercise, but also during day to day activities, and represent a new and unexplored mechanistic link between exercise intolerance and CV risk in CKD. Our long-term goals are to elucidate the mechanisms underlying abnormal hemodynamic responses during physical activity in CKD, which can inform development of therapies that target these underlying aberrancies, improve hemodynamics both at rest and during physical activity, and ultimately improve CV outcomes. We previously showed that the degree of increase in BP for the same degree of increase in sympathetic nerve activity (SNA) during exercise is significantly higher in CKD patients compared to Controls. These findings suggest that CKD patients have an augmented vasoconstrictive response, i.e. greater neurovascular transduction, in response to exercise-induced SNS activation, leading to an augmented exercise pressor response. Aim 1 seeks to elucidate the mechanisms that differentially modulate neurovascular transduction of SNA in CKD. Specifically, we will test the hypothesis that CKD patients have an impaired capacity to oppose SNS-mediated vasoconstriction within exercising skeletal muscle, defined as functional sympatholysis, which is associated with enhanced neurovascular transduction of SNA during exercise. We will also test the hypothesis that CKD patients have heightened vascular ?1-adrenergic receptor (AR) sensitivity, leading to a greater degree of vasoconstriction in response to exercise-induced SNS activation. To translate these studies into the clinical arena, in Aim 2, we will conduct a clinical trial testing the potential benefits of a multifaceted intervention targeting the underlying derangements of impaired functional sympatholysis and heightened vascular ?1-AR sensitivity. Since both functional sympatholysis and vascular ?1-AR sensitivity are modulated by nitric oxide (NO), and CKD patients have decreased NO bioavailability, we will determine if strategies to improve NO bioavailability nonpharmacologically (via aerobic exercise training), and pharmacologically (via tetrahydrobiopterin (BH4) supplementation) improves hemodynamic and neurovascular responses during exercise in CKD. Using a 2x2 factorial design randomized controlled trial, we will test the hypothesis that exercise training and BH4 supplementation independently and synergistically improve the primary outcomes of exaggerated exercise pressor responses, impaired functional sympatholysis, and heightened vascular ?1-AR sensitivity in CKD. These studies will provide important new insights into underlying physiologic derangements that contribute to high blood pressure and increased CV risk in this highly prevalent patient population.